The Impact of T Cell Help on Anti-dsDNA B Cells

描述(申请人提供)：抗dsDNA抗体是 系统性红斑狼疮的诊断标准。要了解如何 这些自体抗体在健康的个体中受到调节，并识别 在自身免疫中表达的潜在机制，我们使用了一种 免疫球蛋白转基因(Ig TG)模型。这种模式的优点是 抗dsDNA B细胞的发展可以在一种 非自身免疫和自身免疫易感(LPR/LPR)患者的不同B细胞谱系 背景。我们提供的数据表明，T细胞在 抗dsDNA B细胞的表型。使用抗体耗竭来去除CD4细胞，我们 已经证明了抗dsDNA B细胞的表型变化 Fas缺陷小鼠--它们的卵泡进入和成熟--依赖T 手机救命。此外，使用模型系统来提供T细胞帮助，我们可以 从抗dsDNA B细胞诱导卵泡进入、成熟和产生抗体 在Fas充足的小鼠中。总体而言，这些结果表明 T细胞帮助的可用性负责确定抗dsDNA B 细胞在功能上处于静默状态或被激活。最后，我们确定了 我们假设的LPR/LPR树突状细胞(DC)的独特属性 在体内产生(自身)反应性T细胞帮助的中心角色。 在这里，我们建议扩大这些初步发现，以确定首先， CD4T细胞的性质有助于年轻Fas缺陷小鼠促进 抗dsDNA B细胞进入卵泡但不能终末分化 T细胞在促进10周龄自身抗体产生中的作用 动物。我们将测试不同类别的T细胞提供T细胞的能力 细胞对Fas充足小鼠BALB/c抗dsDNA B细胞的作用及改变 LPR/LPR小鼠体内自身抗体产生的动力学第二，我们将研究DC 在LPR/LPR小鼠中的功能，并确定DC的变化程度 LPR/LPR小鼠的表型参与自身免疫的启动 继发于T和/或B细胞调节失调。定义符合以下条件的流程 将某些自身反应性B细胞从耐受状态释放出来对于 对自身免疫性疾病的理解和最终的治疗。

DESCRIPTION (provided by applicant): Anti-dsDNA antibodies (Abs) are one of the diagnostic criteria of systemic lupus erythematosus (SLE). To understand how these autoAbs are regulated in healthy individuals and to identify the mechanisms underlying their expression in autoimmunity, we have used an immunoglobulin transgenic (Ig Tg) model. The advantage of this model is that the development of anti-dsDNA B cells can be tracked in the context of a diverse B cell repertoire in non-autoimmune and autoimmune-prone (lpr/lpr) backgrounds. We present data showing that T cells play a determining role in the phenotype of anti-dsDNA B cells. Using Ab depletion to remove CD4 cells, we have demonstrated that the phenotypic changes in anti-dsDNA B cells in Fas-deficient mice - their follicular entry and maturation - are dependent on T cell help. Additionally, using a model system to provide T cell help, we can induce follicular entry, maturation, and Ab production from anti-dsDNA B cells in Fas-sufficient mice. Collectively, these results suggest that the availability of T cell help is responsible for determining whether anti-dsDNA B cells are functionally silent or become activated. Finally, we have identified unique attributes of the lpr/lpr dendritic cells (DCs) that we hypothesize play a central role in generating the (auto)reactive T cell help in vivo. Here, we propose to extend these preliminary findings to identify first, the nature of the CD4 T cell help in young Fas-deficient mice that promotes follicular entry but not terminal differentiation of anti-dsDNA B cells, and the requirements for T cell help in promoting autoAb production in 10-week-old animals. We will test the ability of distinct classes of T cells to provide T cell help to BALB/c anti-dsDNA B cells in Fas-sufficient mice and to alter the kinetics of autoAb production in lpr/lpr mice. Second, we will examine DC function in lpr/lpr mice, and determine the extent to which alterations in DC phenotype in lpr/lpr mice are involved in the initiation of autoimmunity or are secondary to the dysregulation of T and/or B cells. Defining the processes that release certain self-reactive B cells from their tolerant state is critical to the understanding and eventual treatment of autoimmune disease.